Spermine is a ubiquitous and endogenous polyamine that is overexpressed in numerous human tumors. Spermine potently inhibits macrophage activation at physiologic concentrations, and enhanced synthesis and secretion of spermine by tumor cells may play a critical role in the ability of tumors to evade immune-mediated cytotoxicity. Our preliminary studies indicate that, like glucocorticoids, spermine counterregulates proinflammatory cytokine production and may be considered an endogenous immunomodulator capable of stemming local immune responses. Spermine levels required to suppress cytokine synthesis are readily achieved in vivo and high concentrations have been reported in tumors and in infected individuals. We are developing an important class of inhibitors that antagonize the counterregulatory effects of spermine and are immunostimulatory under conditions where the immune response is suppressed by spermine. Furthermore, our preliminary results indicate that these drugs are nontoxic to tumor cells but elicit anti-tumor effects from spermine-treated macrophages in vitro and on B-16 melanoma tumors in vivo. These results suggest that these drugs may act by revealing tumor cells to the host immune system and may benefit cancer patients by promoting endogenous self-healing capacities. We propose to define the mechanisms by which these drugs act on intracellular targets, refine the chemical structure of this class to generate a lead compound having an optimized pharmacological profile, and develop this compound for clinical use. PROPOSED COMMERCIAL APPLICATIONS: The proposal involves development of a novel class of non-toxic anti- cancer agents for treatment of human cancer.